The intermediate processes which couple or transduce the interaction of an effector molecule (e.g., ADP, epinephrine, 5-hydroxytryptamine, etc.) with the platelet membrane into the platelet are unknown. Each of the effector molecules are believed to induce an increase in intraplatelet calcium ion levels. The increase in platelet Ca2 ion induces interaction of platelet actin and myosin and the onset of functional change. As in most cells exhibiting excitation-contraction coupling, the intermediate processes are likely to consist of inward ion movements; e.g., influx of external Ca2 ion, influx of Na ion. We demonstrated that ADP addition to human platelets in plasma induces an inward movement of Na ion but not Ca2 ion. On the other hand, epinephrine addition induces inward movement of Ca2 ion but not Na ion. Thus, the effector response is ion-specific. Our findings have led us to postulate that the ADP excitation-coupling mechanism consists of an increase in Na ion permeability, a dissipation of the Na ion electrochemical transmembrane gradient, associated with the inward movement of Na ion and a rise in intraplatelet Na ion. The rise in intraplatelet Na ion acts to induce intraplatelet calcium redistribution in a manner analogous to muscle. If this view is held it follows that platelet sensitivity to ADP will be a function of the Na ion transmembrane gradient and the rate of Na ion efflux (thus, we found that ouabain, which blocks Na ion efflux, induces hypersensitivity to ADP). We propose to further delineate the characteristics of ADP (and other agonists, e.g., 5-HT) induced inward movement of Na ion and to relate these characterisitics to the induction of functional change.